This invention relates to compositions and methods of alleviating stress and stress related disease in humans and other warm-blooded animals. More particularly, this invention relates to amino acid chelated mineral compositions containing chromium and, optionally, one or more minerals selected from the group consisting of copper, zinc, manganese, iron and selenium and to methods of administering these compositions to influence mineral uptake and absorption in humans and other warm-blooded animals subjected to conditions of stress or exhibiting symptoms of stress.
Stress may be brought on by many factors of which strenuous exercise, physical training, change in environment, infection, dietary irregularity (e.g. elevated glucose and/or low protein intake), increased urinary excretion of chromium and other essential minerals are only exemplary. Conditions of stress in warm-blooded animals may be indicated by a variety of overt symptoms or signs. General malaise, increased morbidity and/or mortality, poor food conversion and/or loss of weight and sterility, among others, are indications of stress. Most forms of stress and disease result in some reduction in feed intake.
In copending application Ser. No. 549,112, it was reported that deficiencies in such minerals as copper, zinc, manganese, iron and selenium could result in increased morbidity and/or reduced immune response. It is reported that zinc deficiency may decrease insulin secretion, increase insulin resistance and/or reduce insulin action. Zinc and copper have also been shown to influence immune response in ruminants and other animals. See Bull, Trace Minerals and Immunology, Western Nutritional Conference, 1990, Gershwin et al., Trace Element Deficiencies and Immune Responsiveness, Trace Elements in Man and Animals (Ed. L. S. Hurley) Plenum Press. N.Y., 1988. Zinc, copper and manganese are the most common trace minerals influencing enzyme systems controlling proper immune functions, Lente, Copper Proteins and Copper Enzymes, Vol. 11, CRC Press, Boca Raton. Fla., 1984. Manganese plays a critical role in carbohydrate metabolism including a requirement in insulin synthesis and release, Gershwin et al., supra. Evidence also suggests that deficiencies in many of the micronutrients such as zinc, copper, chromium and manganese, as well as vitamin B-6, may lead to glucose intolerance.
Chromium functions as a potentiator of insulin. Chromium is a trivalent mineral which has been found in recent years to be more bioavailable when administered as an organic complex. The most common organic complex is a low-molecular weight organic complex termed "glucose tolerance factor" (GTF) obtained primarily from Brewer's yeast. Recent research has shown that various stressors such as infection, strenuous exercise, pregnancy, change of environment, etc, increase urinary excretion of chromium. Suboptimal levels of chromium may be a factor in several stress related diseases. Schnauzer et al., Effects Of Chromium Supplementation in Food Energy Utilization and the Trace-element Composition in the Liver and Heart of Glucose-exposed Young Mice, Biol. Trace Element Res. 9:79 1986, have shown that chromium supplementation protects against stress-induced losses of trace minerals such as zinc, copper, iron and manganese. Polansky et al., Beneficial Effects of Supplemental Chromium on Glucose, Insulin and Glucagon of Subjects Consuming Controlled Low Chromium Diets, FASEB J. A2964. 1990, report that human dietary chromium intakes is suboptimal with diets of approximately twenty-five percent of the U.S. population containing forty percent or less of the recommended daily chromium intake. There is also evidence that chromium in the human body decreases with age. In the animal kingdom, it has been found that steers, subjected to conditions of stress, have increased serum cortisol levels which can be lowered by administration of supplemental chromium.
One particular form of stress in cattle is bovine respiratory disease complex (BRD), also known as "shipping fever". Despite improvements in management feeding and vaccines, a high incidence of this disease still exists and remains one of the most important syndromes affecting the health status of cattle in feedlots, particularly in those feeding calves. BRD is often present in combination with viral and bacterial pathogens which only add to the problems. Buyers continue to suffer the associated loses of shrinkage, treatments costs, inefficient gain and occasional death. The magnitude of these losses and the public concern about indiscriminant use of antibiotics make it imperative that better methods be developed to control this disease complex.
Recent research, particularly with monograstic animals, has shown beneficial effects of various nutrients on immunocompetence and consequent resistance to infectious agents. For example, it has been shown that administration of chromium, tends to suppress the effects of BRD when administered to feeder calves. Chromium supplementation has demonstrated increased weight gain and reduced morbidity in studies carried out in calves shipped from a distant location to a feed lot.
Moreover, chromium is an essential trace element as a co-factor in several enzyme systems. As mentioned above, it is associated with a low-molecular weight organic complex termed "glucose tolerance factor" (GTF) that acts with insulin in promoting normal glucose utilization. Brewer's yeast, which is rich in GTF, has been shown to improve glucose tolerance, lower serum cholesterol and triglycerides in some subjects and to reduce insulin requirements in some diabetics. Glucose tolerance is usually impaired in protein-calorie malnutrition and some cases have shown a dramatic response to administration of trivalent chromium. Deficiency has been reported in patients on prolonged parenteral feeding. Additionally, GTF is not only a co-factor of insulin thus influencing glucose, but protein and lipid metabolism as well. GTF is not as effective, if not ineffective, in the absence of insulin. The exact mechanism by which GTF improves glucose tolerance is not known. However, it is thought that GTF enhances the binding of insulin to its specific receptors.
Elevated cortisol levels are known to suppress the immune system. Cortisol prevents glucose entry into muscle and adipose tissue and decreases activity of insulin. Moreover, cortisol has been shown to inhibit LH release in the bovine species and therefore has an effect on reproduction. Insulin availability may limit the onset of ovarian activity leading to first ovulation. Insulin is also known to reduce concentration of blood ketone bodies. Supplemental chromium, when used to decrease serum cortisol, in dairy cows may increase milk production. Sartin et al., Plasma Concentrations of Metabolic Hormones in High and Low Producing Dairy Cows, J. Dairy. Sci. 71:650-657, 1988 reports that cortisol is antagonistic to milk production. Supplemental chromium also has been found to be associated with weight gain in stressed animals. Part of the improvement in gain with administering supplemental chromium may be due to decreasing cortisol production. It has been shown by Southorn et al., The Effect of Corticosterone Treatment of the Response of Muscle protein Synthesis to Insulin Infusion in the Rat, J. Endocrin. 23:abst. #127, 1989, that rats treated with corticosterone developed insulin resistance with respect to muscle protein synthesis. Clinical evidence supports the immunosuppressive activity of glucocorticoids through impairment of neutrophil function and suppression of lymphocyte blastogenesis.
Another part of the beneficial effects of chromium on the immune system may be related to vitamin C metabolism. It is known that cattle arriving at a feedlot in a chronically stressed condition show evidence of hyperglycemia and are at greater risk of disease as vitamin C entry into neutrophils is most likely reduced. Vitamin C is needed for neutrophil function, decreases circulating corticoid levels and ameliorates immunosuppression in stress. Nockels, Effect of Stress on Mineral Requirements, Western Nutritional Conference, 1990 and Satterlee et al., Vitamin C Amelioration of the Adrenal Stress Response in Broiler Chickens Being Prepared for Slaughter, Comp. Biochem. Physiol., 94A:569-574, 1989 have shown that vitamin C ameliorates the negative effect of stress in broiler chickens being prepared for slaughter which is possibly due to suppression of adrenocortical steroidogenesis. Synthesis of ascorbate from glucose may be reduced when glucose is deficient as in earlier fasting during transport. Calves may also have a low glucose synthesis when fed forage diets so vitamin C synthesis may be low.
Glucocorticoids are known to suppress the immune system according to Munck et al, Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions, Endoc. Rev. 5:25, 1984. Therefore, another beneficial effect of chromium supplementation during periods of stress in suppressing cortisol serum levels could conceivable result in improving effectiveness of certain vaccines. Carlson et al., The Bovine Proceedings, 15:84 1990, measured antibody response to IBR vaccination in feedlot cattle found cattle to be poorly responsive to immunization upon arrival in the feedlot. These results were attributed to the stresses of shipping and respiratory infection drawing the conclusion that such factors may render an animal immunocompetent.
Once chromium is mobilized in response to increased glucose metabolism and/or elevated insulin response, it is not reabsorbed in the tissues but is excreted in the urine. Therefore, diets that lead to elevated circulating insulin will lead to chromium depletion.
As shown by U.S. Pat. No. 4,954,492, there have been numerous attempts to prepare synthetic trace metal complexes which exhibit GTF activity to mimic or enhance the GTF activity found in Brewer's yeast. This research has primarily centered around the use of chromium complexed with nicotinic acid and amino acids.
In addition to conditions of metabolic stress, viral and other infections sometimes overwhelm the immune system leading to secondary complications which tend to exacerbate the primary stress symptoms. For example, some infections cause morphological changes in the intestine which result in malabsorption which may hinder the uptake of essential trace minerals and/or the metallic co-factors which are beneficial for immune system functioning. A common site of intestinal abnormality is the duodenum, the portion of the small intestine where metal ions are primarily absorbed under normal conditions. Since the pH in the duodenum is acidic, metal ions are present in soluble ionic form. As these ions pass along the intestinal tract, the Ph in the jejunum becomes more basic and absorption of metals in ionic form becomes more difficult. Diarrhea is also a common problem associated with many infections due to the profuse fluid secretion in the duodenum and proximal jejunum resulting in malabsorption of minerals.
One factor which may contribute to the malabsorption of minerals, exacerbated by conditions of stress, is that ionic mineral absorption requires an integral protein carrier molecule embedded in and transversing the mucosal membrane. Once absorbed into the mucosal cell the transfer of the cation from the terminal web below the microvilli to the basement membrane requires the presence of carrier proteins. For iron and most minerals apoferritin is a suitable carrier. In the case of zinc, albumin is the carrier protein. For copper the carrier is ceruloplasmin and for manganese it is transmanganin. If, due to stress or lack of proper mineral availability, the metabolic system of an animal is suppressed or does not function properly the chemistry of the cells is altered and the cells do not perform their tasks due to mineral deficiencies.
From the above it is evident proper metabolic functioning of chromium and also other minerals such as copper, zinc, manganese, iron and selenium are known to play an important role in maintaining the health and vigor of an animal. Moreover, it is also evident that there may be metabolic dysfunctioning of cells on the surface of the intestinal lumen to the point that these minerals may not be adequately absorbed in warm-blooded animals, including humans. This could occur if the animal were suffering from conditions of stress which affected the portion of the intestine where mineral ions were most likely to be absorbed, i.e. the duodenum. Over a period of time, the inability of the body to absorb these minerals would result in compromising proper metabolic functioning and allowing secondary diseases to be introduced into the body. It would therefore be beneficial to provide chromium and, if desired, other essential minerals to warm-blooded animals subjected to conditions of stress and/or exhibiting symptoms of metabolic dysfunctioning known to be brought on by stress in a bioavailable form in which such minerals would be absorbed via a pathway which did not require duodenal absorption in ionic form.
Ashmead et al., U.S. Pat. No. 4,020,158; Ashmead, U.S. Pat. No. 4,076,803; Jensen U.S. Pat. No. 4,167,564; Ashmead, U.S. Pat. No. 4,774,089 and Ashmead, U.S. Pat. No. 4,863,898 all teach various uses for amino acid chelates in reference to increasing absorption of essential minerals into biological tissues. Some of these patents suggest that certain mineral and ligand combinations can enhance metal uptake in specific organs or tissues where specific biological functions are enhanced, i.e. minerals crossing the placental membranes into foeti, estrus or spermatogenesis, etc. However, it has not heretofore been known that administration of chromium, in chelated form, administered alone or in combination of other metal amino acid chelates can have a positive effect in reducing serum cortisol levels and otherwise alleviating conditions of stress.